With the deepening of tumor genetics and biology research, multiple intracellular tumor-related key signaling pathways have been found. Tumor cells rely on these pathways to achieve intracellular transduction of extracellular signals and regulate their own sustained proliferation, invasion, metastasis, anti-apoptosis, and other activities, thereby maintaining their malignant phenotypic characteristics on one hand and gaining tolerance against treatment through regulating specific genes and protein products thereof on the other hand. Studies have revealed that the transduction pathway mediated by the phosphatidylinositol 3-kinase (PI3K)-AKT-mammalian rapamycin target (mTOR) plays an important role in some cellular processes including proliferation and survival, and malfunction of these pathways is pathogenic factor for a wide range of human cancers and other disease profiles (Katso et al., Annual Rev. Cell Dev. BioL, 2001, 17: 615-617).
Phosphatidylinositol 3-kinase (PI3K) belongs to the family of lipokines and can be divided into three classes according to their structural characteristics and substrate selectivity. Class 1 PI3K, the most intensively studied, is a heterodimer protein which is composed of subunits with catalytic function (ρ110α, ρ110β, ρ110δ, and ρ110γ) and subunits with regulatory function (ρ85α, ρ85β, ρ50α, ρ55α, and ρ55γ), respectively. Type 1a PI3K enzyme subunits ρ100α and ρ100β are always co-expressed in various cell types, while the expression of ρ110δ is more restricted by leukocyte populations and some epithelial cells. Type 1b PI3K enzyme consists of ρ110γ catalytic subunit interacting with ρ101 regulatory subunit, and mainly distributes in leukocytes, platelets and cardiomyocytes. ρ85 regulatory subunit is activated via phosphorylation through interaction with the receptor tyrosine kinase. The amino terminus of ρ85 contains a SH3 domain and a proline enriched region which is capable of binding to the SH3 domain, and its carboxyl terminus contains two SH2 domains and one ρ110-binding region. The ρ110 subunit has homology with protein kinase, and this subunit itself has both serine/threonine protein kinase activity and phosphatidylinositol kinase activity, and can convert phosphatidylinositol diphosphate (PI2P) to phosphatidylinositol triphosphate (PI3P), wherein the latter can in turn activate a number of downstream signaling molecules, thereby accomplishing the continuing transmission of extracellular signals.
Studies have shown that Type 1a PI3K enzymes can directly or indirectly promote the occurrence of human cancer (Vivanco and Sawyers, Nature Reviews Cancer, 2002, 2, 489-501). For example, gene PIK3CA is widely amplified or mutated in various cancers, and the activation mutations in the catalytic site of the ρ110α subtype encoded by this gene are associated with various other tumors such as tumors of colon or rectum, mammary gland and lung. The expression of ρ110β is approximately 5% amplified in severe epithelial ovarian cancer, breast cancer and PTEN-lacking tumor cell lines. ρ110δ is associated with immunosuppression and is commonly used in transplant rejection and autoimmune diseases. In addition to the direct effect, Type 1a PI3K can indirectly trigger tumors by causing a variety of downstream signaling events. For example, by activating Akt, PI3K-mediated signaling events are enhanced, leading to various cancers. A large number of studies have shown that different PI3K subtypes have different roles and the best way to inhibit the growth of malignant cells is to choose the inhibitors that are more specific to a certain ρ110 subtype than to broadly suppress all Type I PI3K enzymes (Susan and Kenneth, Cancer Treatment Reviews, 2013 Aug. 26. pii: S0305-7372 (13) 00171-0). Currently, unavoidable side effects have been observed for non-selective PI3K inhibitors in clinic, including nausea, vomiting, diarrhea, fatigue, elevated transaminases, hyperglycemia and the like which are commonly seen for PI3K inhibitors. Among the PI3K selective inhibitors, since PIK3CA/ρ110α is the most common PI3K mutant subtype, the PI3Kα selective inhibitors are also the ones that potentially have the most potent tumor-suppressing effect. At the same time, PI3Kα selective inhibitors can also, to the greatest extent, avoid pneumonia, neutropenia, thrombocytopenia, anemia, elevated transaminase and other side effects caused by PI3Kβ and PI3Kδ inhibitors in clinic (Brana and Siu, BMC Medicine, 2012, 10: 161).
PI3K is a key regulatory pathway for cell function. Its abnormal signaling is closely related to the activation of proto-oncogene, and PI3K thus has a critical effect on the onset and development of tumor. Therefore, it can be expected that developing small molecule compounds to inhibit PI3K as a tumor treatment drug has a promising prospect.
For PI3K signaling pathways, there are currently a number of compounds independently inhibiting PI3K activity under development and clinical trials. For example, the PI3K inhibitor, BKM-120, developed by Novartis, is now in phase III clinical stage for breast cancer. Another PI3K inhibitor, BYL-719, developed by Novartis for the treatment of solid tumors, and head and neck cancer, is also in clinical phase III now.

Therefore, the development of medicaments against PI3K with higher activity, better selectivity, and less toxicity is of great significance.